Noninvasive glucose sensing methods and systems

ABSTRACT

New methods and systems for noninvasive glucose monitoring and sensing with electromagnetic waves or ultrasound are disclosed. The methods are based on absolute or relative measurement of tissue dimensions (or changes in the dimensions) including, but not limited to: thickness, length, width, diameter, curvature, roughness as well as time of flight of ultrasound and optical pulses and optical thickness, which change with changing blood glucose concentrations. By measuring noninvasively absolute or relative changes in at least one dimension of at least one tissue or tissue layer or absolute or relative changes in time of flight of ultrasound or optical pulses, one can monitor blood glucose concentration noninvasively.

RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/760,741, filed 20 Jan. 2006.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for noninvasive glucosesensing and a system for implementing the method.

More particularly, the present invention relates to a method fornoninvasive glucose sensing including the step of measuring a thicknessof a target tissue or a time of flight of ultrasound or optical pulsesin the target tissue and determining a glucose value from the thicknessof the target tissue or the time of flight in the target tissue inaccordance with a target tissue thickness or time of flight versusglucose calibration curve and a system for implementing the method.

2. Description of the Related Art

Other techniques can be used for tissue dimension measurement. Nearinfrared absorption spectroscopy can provide tissue thicknessmeasurement (U.S. Pat. No. 6,671,542). However, techniques with higherresolution are needed for accurate glucose monitoring. One can useoptical refractometry (U.S. Pat. No. 6,442,410) for noninvasive bloodglucose measurement. However, this technique has limitations associatedwith low accuracy and specificity of glucose monitoring.

U.S. Pat. No. 7,039,446 B2 discloses a variety of techniques for analytemeasurements but does not disclose how to measure tissue thickness anduse the thickness measurements for glucose concentration monitoring.Acoustic velocity measurement in blood was proposed in U.S. Pat. No.5,119,819 for glucose monitoring. However, tissue thickness measurementswere not disclosed. Photoacoustic techniques were proposed in U.S. Pat.No. 6,846,288 B2 for measurement of blood glucose concentration bygenerating photoacoustic waves in blood vessels.

These and other techniques proposed for noninvasive glucose monitoringhave limited accuracy and specificity.

Thus, there is still a need in the art for simple noninvasive glucosesensing methods and systems.

SUMMARY OF THE INVENTION

The present invention provides a blood glucose monitoring technique thatis critically important for diabetic patients. Tight glucose controldecreases dramatically complications and mortality associated withdiabetes. Blood glucose monitoring is an important part of blood glucosecontrol. At present, all techniques for blood glucose monitoring areinvasive and require a drop of blood or interstitial fluid formeasurement.

The present invention also provides a noninvasive blood glucosemonitoring technique that would also be invaluable in critically illpatients, regardless of whether those patients are diabetic. Clinicalstudies clearly establish that morbidity and mortality are reduced inpatients requiring intensive care if blood glucose is tightly controlledbetween 80 and 110 mg/dL (Van den Berghe G, 2005; Vanhorebeek I, 2005;van den Berghe G, 2001). However, conventional techniques for tightlycontrolling blood glucose have several limitations, including the needfor frequent blood sampling and the risk that insulin administrationwill induce hypoglycemia (blood glucose <60 mg/dL) between samplingintervals and that hypoglycemia therefore will not be promptly diagnosedand treated. A continuous method of monitoring blood glucose bymeasuring tissue thickness would greatly improve the ease and safety oftightly controlling blood glucose with insulin in critically illpatients.

The measurement of dimensions or time of flight can be performed in avariety of tissues including, but not limited to: skin tissues (dermis,epidermis, subcutaneous fat), eye tissues (lens, anterior chamber,vitreous cavity, eye ball, sclera), mucosal tissues, nailbed, lunula,connective tissue, muscle tissue, blood vessels, cartilage tissue,tendon tissue. The dimension(s) of these tissues can change with bloodglucose concentration. For instance, our studies demonstrated thatincrease of blood glucose concentration may decrease the thickness (andoptical thickness) of and time of flight of ultrasound pulses in theskin tissues (namely, dermis). Measurements of dimensions of specifictissue layers (within one of these tissues) can be used for glucosemonitoring. Measurement of one, two or more dimensions can be performedfor more accurate, specific, and sensitive glucose monitoring. Ratios ofdimensions of two or more tissues can be used for more robust, accurate,specific, and sensitive glucose monitoring. For instance, increasingblood glucose concentration may increase lens thickness and decreaseanterior chamber thickness (Furushima et al., 1999). The ratio of thesechanges may provide robust, accurate, and sensitive blood glucosemonitoring. One can use measurement of total dimensions of complextissues consisting on two or more different tissues. Measurement of timeof flight of ultrasound or optical waves in these tissues, or opticalthickness of these tissues can also be used for non-invasive glucosemonitoring without calculating or determining geometrical thickness orother dimensions of these tissues.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdetailed description together with the appended illustrative drawings inwhich like elements are numbered the same:

FIG. 1 depicts an embodiment of an ultrasound system for tissuethickness or ultrasound time of flight measurement.

FIG. 2 depicts a typical ultrasound signal from the skin/subcutaneoistissue interface from a human subject (forearm area) recorded by thesystem of this invention.

FIG. 3 shows blood glucose concentration (solid circles) in a humansubject before and after a sugar drink at the 20^(th) minute (76 g ofsugar in 650 mL of water).

FIG. 4 depicts similar in vivo results before and after a higher glucoseload (108 g of sugar in 1 L of water) at 25^(th) minute. Themeasurements were performed with the same ultrasound system from thesubject's forearm. The data show good correlation of the signal shift(and, therefore, time of flight of ultrasound pulses in the skin) withblood glucose concentration.

FIG. 5 depicts an embodiment of an optical system for noninvasiveglucose monitoring using tissue thickness measurement by a focusing lenswith in-depth mechanical scanning. Light from a laser or other opticalsource is focused on the tissue layers. When focus position coincideswith tissue boundary, a peak of reflection is induced and is recorded bya photodetector (PD).

FIG. 6 depicts an optical system for noninvasive glucose monitoringusing tissue thickness measurement by a focusing lens with in-depthelectrooptical scanning. Light from a laser or other optical source isfocused on the tissue layers. When focus position coincides with tissueboundary, a peak of reflection is induced and is recorded by aphotodetector (PD).

FIG. 7 depicts an optical system for noninvasive glucose monitoringusing tissue thickness measurement with a pinhole and a focusing lenswith scanning. Light from a laser or other optical source is focusedthrough the pinhole on tissue layers. When focus position coincides withtissue boundary, a peak of reflection is induced and is recorded by aphotodetector (PD) through the pinhole.

FIG. 8 depicts an optical system for noninvasive glucose monitoringusing tissue thickness measurement with a fiber-optic system and afocusing lens with scanning. Light from a laser or other optical sourceis focused through the fiber-optic system on tissue layers. When focusposition coincides with tissue boundary, a peak of reflection is inducedand is recorded by a photodetector (PD) through the fibers.

FIG. 9 depicts a time-resolved optical system generating ultrashort(typically femtosecond) optical pulses, directing the pulses to thetissues, and detecting the pulses reflected from tissue layers. Thesystem measures the time of flight of the optical pulses and convertsthem into blood glucose concentration.

FIG. 10 depicts an optoacoustic system for time of flight or thicknessmeasurements. At least one short (typically nanosecond or picosecond)optical pulse is generated by the system, directed to the tissue,generates ultrasound waves in the tissues. An ultrasound transducerdetects the ultrasound waves and the ultrasound signal is analyzed by aprocessor. The optically-induced ultrasound waves carry information onthe ultrasound time of flight in tissue layers. The geometricalthickness can be calculated by multiplying the time of flight by speedof sound. A short radiofrequency (typically nanosecond) pulse can beused instead of the optical pulse to generate the ultrasound waves.

FIG. 11 depicts an optical system for generating short, broad-bandultrasound pulses in an optically absorbing medium. The medium isattached to the tissue surface. The optical system produces at least oneshort (typically nanosecond or picosecond) optical pulse and directs iton the absorbing medium. The energy of the optical pulse is absorbed bythe medium that results in generation of a short ultrasound (acoustic)pulse. The ultrasound pulse then propagates in the tissue and isreflected from tissue layers. An ultrasound transducer detects thereflected ultrasound pulses and a processor analyzes the signal from thetransducer and calculates the time of flight of the ultrasound pulsesand glucose concentration. A short (typically nanosecond) radiofrequencyelectromagnetic pulse can be used instead of the short optical pulse togenerate a short, broad-band ultrasound pulse in a radiofrequencyabsorbing medium.

DETAILED DESCRIPTION OF THE INVENTION

The invention discloses method and apparatus for noninvasive glucosemonitoring and sensing with electromagnetic (including optical) waves orultrasound. This method is based on absolute or relative measurement oftissue dimensions (or changes in the dimensions) including, but notlimited to: thickness, length, width, diameter, curvature, roughness aswell as optical thickness and time of flight of optical or ultrasoundpulses. Changes in blood glucose concentration may increase or decreasetissue dimensions due to a variety of possible mechanisms. One of themis the glucose-induced osmotic effect. The osmotic effect may decreaseor increase tissue dimension(s) depending on tissue type, structure,location, condition, cell density, blood content, and vascularization.By measuring noninvasively absolute or relative changes in at least onedimension of at least one tissue or tissue layer, one can monitor bloodglucose concentration noninvasively. Variation of glucose concentrationmay also change sound velocity and refractive index. Thus, themeasurement of time of flight of the ultrasound or optical pulses mayprovide more robust, accurate, and specific monitoring of blood glucoseconcentration compared to geometrical dimension measurements.

Tissues include, but are not limited to: skin tissues (dermis,epidermis, subcutaneous fat), eye tissues (lens, anterior chamber,vitreous cavity, eye ball, sclera), mucosal tissues, nailbed, lunula,connective tissue, muscle tissue, blood vessels, cartilage tissue,tendon tissue. The dimension(s) of these tissues can change with bloodglucose concentration. For instance, our studies demonstrated thatincrease of blood glucose concentration may decrease the time of flightin and thickness of the skin tissues (namely, dermis). Measurements ofdimensions of specific tissue layers (within one of these tissues) canbe used for glucose monitoring. Measurement of one, two or moredimensions can be performed for more accurate, specific, and sensitiveglucose monitoring. Ratio of dimensions of two or more tissues can beused for more robust, accurate, specific, and sensitive glucosemonitoring. For instance, increase of blood glucose concentration mayincrease lens thickness and decrease anterior chamber thickness(Furushima et al., 1999). The ratio of these changes may provide robust,accurate, and sensitive blood glucose monitoring. One can usemeasurement of total dimensions of complex tissues consisting on two ormore different tissues. Measurement of optical thickness of thesetissues can also be used for non-invasive glucose monitoring.

The electromagnetic wave or ultrasound with at least one wavelength(frequency) is directed to the tissue or tissue layer. Reflected,refracted, transmitted, scattered, backscattered, or forward-scatteredwave can be used for measurement of the tissue dimensions. Themeasurements of tissue dimensions can be performed in the reflectionmode or in the transmission mode. In the reflection mode, irradiationand detection are performed from one side. In the transmission mode,irradiation and detection are performed from different sides.

The electromagnetic waves include optical radiation (near infrared,infrared, far infrared, visible, and UV light in the wavelength rangefrom about 200 nanometers to about 100 microns), terahertz waves,microwaves, radiowaves, low-frequency waves, static electric or magneticfiled. A combination of different waves can be used with one, two, ormultiple wavelengths (frequencies) can be used for more accurate,specific, and sensitive glucose monitoring.

Ultrasound includes ultrasonic waves in the frequency range from about20 kHz to about 10 Gigahertz. One, two, or multiple frequencies orbroad-band ultrasound pulses can be used for more accurate, specific,and sensitive glucose monitoring. The broad-band ultrasound pulses canbe generated by using short electromagnetic pulses irradiating astrongly absorbing medium attached to the tissue. Short optical pulsesinduced by laser and non-laser sources can be used for generation of thebroad-band ultrasound pulses.

Combination of electromagnetic waves and ultrasound may provide higheraccuracy and specificity of glucose monitoring. Hybrid techniques suchas optoacoustics and thermoacoustics can be used for tissue dimension ortime of flight measurement. Short optical pulses from laser or non-lasersources or short radiofrequency pulses can be used for generatingacoustic waves in the tissue. Acoustic (ultrasound) detectors,preferably, broad-band detectors can be used for detection of theacoustic waves. The time of flight (and glucose-induced signal shift)can be measured by analyzing the optoacoustic and thermoacoustic waves.One can calculate tissue thickness, L, by using the formula: L=ct, wherec is the speed of sound in tissue. In contrast to the formula presentedabove for the pure ultrasound technique, the factor of ½ is not usedbecause the optoacoustic or thermoacoustic waves propagate only one way(from tissue to detector). For additional information on optoacousticsthe reader is referred to U.S. Pat. Nos. 6,751,490, and 6,498,942,incorporated herein by reference.

The electromagnetic waves and ultrasound can be pulsed, continuous wave,or modulated. Amplitude and/or frequency can be modulated to providehigh signal-to-noise ratio.

The measurements can be performed with one or more (array) of detectorsof electromagnetic or ultrasound waves. One can use multiple sources ofelectromagnetic waves or ultrasound for glucose monitoring.

Combination of these techniques with other techniques may provide moreaccurate, specific, and sensitive glucose monitoring.

The glucose sensing device can be wearable to provide continuousmonitoring. A wearable device (like a wrist watch) can be used forcontinuous skin thickness measurement. One can use specially-designedglasses for glucose monitoring systems based on eye tissue thickness ortime of flight measurement.

The glucose-sensing probe(s) attached to the tissue can be controlled bya radiofrequency controller remotely to minimize patient's discomfort.Light-weight probes can be used to decrease pressure applied by theprobe on the tissue surface and improve accuracy of glucose monitoring.

The tissue temperature should be stabilized and be, preferably, in therange from about 37° C. to about 40° C. A temperature controller with aheater should be used to provide a stable temperature in this range. Thestable temperature yields constant speed of sound and refractive index,and therefore, more accurate and specific glucose monitoring. Moreover,tissue warming to these temperatures improves blood flow and glucosetransport in the tissues that yield to more accurate and specificglucose monitoring.

General Information

The inventors disclose monitoring blood glucose concentrationnoninvasively by measuring absolute or relative tissue dimensions (orchanges in the dimensions) including, but not limited to: thickness,length, width, diameter, curvature, roughness as well as time of flightof ultrasound and electromagnetic pulses and optical thickness. Theinventors disclose the use of electromagnetic or ultrasound techniquesfor tissue dimension measurement and, in particular, time of flighttechniques based on generation of short and ultrashort ultrasound orelectromagnetic pulses, focused light reflection technique andfocus-detection technique for noninvasive measurement of tissuethickness as well as other techniques based on detection of reflected,refracted, transmitted, scattered, backscattered, or forward-scatteredwave. The inventors have demonstrated in vivo that time of flight ofultrasound pulses in skin and skin thickness decrease with blood glucoseconcentration. The inventors disclose the use of measurement of time offlight and dimensions of skin tissues (dermis, epidermis, subcutaneousfat), eye tissues (lens, anterior chamber, vitreous cavity, eye ball,sclera), mucosal tissues, nailbed, lunula, connective tissue, muscletissue, blood vessels, cartilage tissue, tendon tissue for noninvasiveglucose monitoring. The inventors disclose the use of optoacoustic andthermoacoustic techniques for tissue time of flight and dimensionmeasurements. The inventors disclose the use of time of flight changes(signal shift) and ratio of dimensions (or changes in dimensions) ofdifferent tissues for more accurate glucose monitoring. The inventorsdisclose the use of two or more wavelengths (frequencies) for moreaccurate glucose monitoring. The inventors disclose the use ofbroad-band ultrasound pulses generated by optical pulses inoptically-absorbing media or generated by radiofrequency pulses inradiofrequency absorbing media. The inventors disclose the use oftime-resolved techniques based on reflection of ultrashort opticalpulses from tissue layers and interfaces. The inventors also disclosethe use of this technique for noninvasive blood glucose monitoring incritically ill patients, regardless of whether those patients arediabetic. Clinical studies clearly establish that morbidity andmortality is reduced in patients requiring intensive care if bloodglucose is tightly controlled between 80 and 110 mg/dL (Van den BergheG, 2005; Vanhorebeek I, 2005; van den Berghe G, 2001). However,conventional techniques for tightly controlling blood glucose haveseveral limitations, including the need for frequent blood sampling andthe risk that insulin will induce hypoglycemia between samplingintervals and that hypoglycemia will not be promptly diagnosed andtreated. A continuous method of monitoring blood glucose by measuringskin thickness or time of flight would greatly improve the ease andsafety of tightly controlling blood glucose with insulin therapy incritically ill patients.

The inventors also disclose the use of combined measurement of time offlight of ultrasound or optical pulses with measurement of attenuation,phase, and frequency spectrum of the ultrasound or optical pulsesreflected from the tissues to improve accuracy and specificity ofglucose monitoring. The attenuation can be measured by analyzing theamplitude of the reflected pulses. The phase and the frequency spectrumcan be measured by analyzing the temporal characteristics of thereflected pulses. The amplitude (attenuation), phase, and frequency ofthe reflected pulses may vary with glucose concentration. Measurement ofthese parameters or glucose-induced changes in these parameters mayprovide additional information which combined with the time of flightmeasurements can be used for more accurate and specific glucosemonitoring.

Blood glucose monitoring is critically important for diabetic patients.Tight glucose control decreases dramatically complications and mortalityassociated with diabetes. Blood glucose monitoring is an important partof blood glucose control. At present, all techniques for blood glucosemonitoring are invasive and require a drop of blood or interstitialfluid for measurement.

There are no techniques for noninvasive glucose monitoring on themarket. The disclosed technique is novel because glucose-induced changesin tissue dimensions or time of flight have not been studied yet. Thisinvention is not obvious to a person having ordinary skill in the art towhich this invention pertains. It is necessary to understand anddemonstrate why and how changes in blood glucose concentration decreaseor increase tissue dimensions or time of flight of ultrasound or opticalpulses.

The broadest application is noninvasive blood glucose monitoring indiabetic patients. However, continuous monitoring of blood glucose incritically ill patients would contribute a separate, clinicallyinvaluable tool in patients who are not diabetic.

The noninvasive glucose monitoring of this invention can be performed byusing a variety of techniques. The following examples are shown todemonstrate possible approaches to glucose monitoring by using dimensionor time of flight measurements with different techniques in varioustissues.

Referring now to FIG. 1, an embodiment of a system of this invention,generally 100, is shown to include an ultrasound transducer 102 inelectrical communication or connected electronically or electrically toa pulser/receiver (P/R) 104. The P/R 104 generates at least oneelectrical pulse which is converted into an ultrasound pulse by thetransducer 102. The ultrasound pulse propagates in a tissue 106 and isreflected from tissue layers 108 a&b due to an acoustic impedancedifference (mismatch) between the layers 108 a&b. The reflectedultrasound pulses are detected by the transducer 102 and analyzed by theP/R 104 to calculate the time of flight or thickness of the layers 108a&b. The time of flight or thickness (or their changes) is thenconverted into glucose concentration or changes in glucose concentrationby using a processor and glucose concentration is displayed by adisplay. The processor and display can be incorporated in thepulser/receiver in one casing or connected to the pulser/receiver usingwires or using wireless radiofrequency communication.

Referring now to FIG. 2, a 20-MHz non-focused piezoelectric transducerwas used to generate short ultrasound pulses. The signal is resultedfrom acoustic impedance mismatch between the skin and subcutaneoustissue. The time of flight of the ultrasound pulses from the upper skinsurface to the skin/subcutaneous tissue interface and back, t, is equalto 1.65 μs (microsecond). This time of flight varies with glucoseconcentration. Glucose-induced changes in skin result in temporal shiftof the signal, Δt, due to the changes in the time of flight. Bymeasuring the signal shift one can monitor glucose concentration. Thiscan be done without calculating the geometrical thickness of the skin(or any other tissue). Thus, the system can monitor glucoseconcentration by measuring the time of flight of the ultrasound pulses(waves) t or changes in the time of light Δt. One can calculate skinthickness, L, by using the formula: L=ct/2, where c is the speed ofsound in skin and factor of ½ is due to the propagation of theultrasound pulse from the skin surface to the interface and back. Theskin thickness measured with this system is equal to L=1.5 mm/μs×1.65μs/2=1.24 mm assuming that c=1.5 mm/μs (typical speed of sound in softtissues).

Referring now to FIG. 3, blood glucose concentration was measured with astandard invasive technique involving blood sampling from finger tipswith a lancet. The ultrasound system shown in FIG. 1 was used to measuretime of flight of ultrasound waves in skin t and changes in the time offlight Δt (the signal shift). The transducer was attached to thesubject's forearm and detected continuously the ultrasound pulsesreflected from the skin/subcutaneous tissue interface. The shift of thesignals recorded at the time of blood sampling (and, therefore, the timeof flight of ultrasound pulses in the skin) closely follows bloodglucose concentration. The time of flight decreased with increase ofblood glucose concentration. The positive signal shift plotted in thegraph corresponds to decrease of the time of flight, while negativevalues of the signal shift correspond to increase of the time of flight.

Referring now to FIG. 5, another embodiment of a system of thisinvention, generally 500, is shown to include an is shown to include apulsed laser light source 502, which produces a pulse beam 504. Thepulsed beam 504 passes through a mechanically scanning lens 506 andimpinges on a tissue site 508 having layers 510 a&b. When focus positioncoincides with a tissue boundary, a peak of reflection 512 a-c isinduced and is recorded by a photodetector (PD) 514.

Referring now to FIG. 6, another embodiment of a system of thisinvention, generally 600, is shown to include an is shown to include apulsed laser light source 602, which produces a pulse beam 604. Thepulsed beam 604 passes through a focusing with in-depth electroopticalscanning lens 606 and impinges on a tissue site 608 having layers 610a&b. When focus position coincides with a tissue boundary, a peak ofreflection 612 a-c is induced and is recorded by a photodetector (PD)614.

Referring now to FIG. 7, another embodiment of a system of thisinvention, generally 700, is shown to include an is shown to include apulsed laser light source 702, which produces a pulse beam 704. Thepulsed beam 704 passes through a first lens 706, then through a pinhole708; and finally, through a focusing with in-depth electroopticalscanning lens 710. The focused beam 712 then impinges on a tissue site714 having layers 716 a&b. When focus position coincides with a tissueboundary, a peak of reflection 720 a-c is induced at each boundary. Thereflects come back through the scanning lens 710, then the pinhole 708,then the first lens 706 to a dichromic 722 to a photodetector (PD) 724,where is the reflected beam is record and analyzed.

Referring now to FIG. 8, another embodiment of a system of thisinvention, generally 800, is shown to include an is shown to include apulsed laser light source 802, which produces a pulse beam 804. Thepulsed beam 804 passes through a first lens 806, then into a fiberoptics fiber 808 and then into a splitter 810. After exiting thesplitter 810, the beam 804 proceeds through a second lens 812 and thenthrough a focusing with in-depth electrooptical scanning lens 814. Thefocused beam 816 then impinges on a tissue site 818 having layers 820a&b. When focus position coincides with a tissue boundary, a peak ofreflection 824 a-c is induced at each boundary. The reflects come backthrough the scanning lens 814, then the second lens 812 to the beamsplitter 810 to a photodetector (PD) 826, where is the reflected beam isrecord and analyzed.

EXPERIMENTAL SECTION OF THE INVENTION Example 1

Glucose-induced changes in skin thickness or time of flight measuredwith electromagnetic techniques.

Glucose-induced changes in skin tissue thickness (optical thickness) canbe measured by using electromagnetic waves including, but not limitedto: optical radiation, terahertz radiation, microwaves, radiofrequencywaves. Optical techniques include but not limited to reflection, focusedreflection, refraction, scattering, polarization, transmission,confocal, interferometric, low-coherence, low-coherence interferometrytechniques.

A wearable, like a wrist watch, optical-based glucose sensor can bedeveloped.

Example 2

Glucose-induced changes in time of flight in and thickness of skinmeasured with ultrasound techniques.

Glucose-induced changes in skin tissue thickness and time of flight canbe measured by using ultrasound waves in the frequency range from 20 kHzto 10 Gigahertz. These techniques include but not limited to reflection,focused reflection, refraction, scattering, transmission, confocaltechniques. It is well known that by using high frequency ultrasound canprovide high-resolution images of tissues. One can use ultrasoundfrequencies higher than 10 MHz for measurement of skin thickness andtime of flight.

FIGS. 1 to 4 show the system, the typical signal from skin/subcutaneoustissue interface, and glucose-induced signal shift (changes in time offlight) measured by the system. A wearable, like a wrist watch,ultrasound-based glucose sensor can be developed.

Example 3

Glucose-induced changes in skin thickness and time of flight measuredwith optoacoustics or thermoacoustic techniques.

Glucose-induced changes in skin tissue thickness and time of flight canbe measured by using optoacoustic or thermoacoustic techniques which mayprovide accurate tissue dimension measurement when short electromagnetic(optical or microwave) pulses are used in combination with wide-bandultrasound detection. FIG. 10 shows such a system. Optical detection ofthe ultrasound waves can be used instead of the ultrasound transducer.

Example 4

Glucose-induced changes in the lens and anterior chamber thicknessmeasured with optical techniques.

One can use measurement of eye tissue thickness (including opticalthickness) with optical techniques for noninvasive and accurate glucosemonitoring. The preferred embodiment is glucose monitoring by measuringthickness of the lens and/or anterior chamber or their ratio by usingnon-contact reflection techniques, preferably with focused lightreflection technique. The focused reflection technique utilizes focusedlight for tissue irradiation and detection of reflection peaks (maxima)when the light is focused on tissue surfaces. If the focus is scanned indepth, one can measure tissue thickness by recording and analyzing thepeaks of reflections during the scanning. This technique allows formeasurement of tissue thickness with high (submicron) accuracy. One canuse multiple detectors to increase signal-to-noise ratio and, therefore,accuracy of glucose monitoring. This technique can be used for tissuethickness measurement (as well as optical thickness measurements) inother tissues (not only eye tissues).

The focused light reflection technique in its simplest form can utilizea light beam focused with a lens on a tissue surface and detection ofthe reflected light with at least one optical detector positioned at asmall angle with respect to the incident beam. By in-depth scanning thefocus, one can detect peaks of reflected light intensity when the focusreaches a tissue surface, or a tissue layer surface. FIG. 5 shows such asystem which utilizes a lens with mechanical scanning. One can use alens with electrooptical scanning that provides fast in-depth scanningand with no moving parts (FIG. 6). A voltage is applied to the lens tovary the focus position within the tissue by using electroopticaleffects.

Another modification of this technique is to use a pinhole that mayprovide higher signal-to-noise ratio by reducing stray light andbackground tissue scattering light (FIG. 7). Instead of a pinhole onecan use a fiber-optic system (FIG. 8) that may provide highsignal-to-noise ratio too. Similar fiber-optic system was used byZeibarth et al. It was demonstrated that such a system can measure eyetissue thickness (including the lens) with high (submicron) accuracy(Zeibarth et al.).

Furushima et al. demonstrated using ultrasound techniques (withsubmillimeter resolution) that the thickness of the lens increases,while thickness of anterior chamber decreases with blood glucoseconcentration. Therefore, one can monitor noninvasively glucoseconcentration with high accuracy and sensitivity by using themeasurement of lens and anterior chamber thickness with either thefocused light reflection technique or the focus-detection technique. Thesystem (either the focused light reflection system or thefocus-detection system) can be assembled on glasses or other wearabledevice to provide convenient and continuous measurement.

Example 5

Glucose-induced changes in the lens and anterior chamber thicknessmeasured with ultrasound techniques.

High frequency ultrasound (>10 MHz) can be used for glucose monitoringbased on measurement of the lens and/or anterior chamber thickness ortime of flight in these tissues. Focused reflection technique utilizingfocused ultrasound can be applied too to provide higher resolution.

Example 6

Glucose-induced changes in the skin or lens and anterior chamberthickness or time of flight measured with optoacoustic or thermoacoustictechniques (FIG. 10).

The optoacoustic and thermoacoustic techniques can provide acceptableaccuracy of the thickness or time of flight measurement in these tissuesif short optical (or microwave, or radiofrequency) pulse are used forgeneration of the thermoelastic waves and if detection of these waves isperformed with wide-band, high-frequency ultrasound detectors. Focusedradiation can be used to provide better accuracy of measurement.

Optical detection of the optoacoustic or the thermoelastic waves can beused to provide non-contact measurement of the optoacoustic and thethermoelastic waves. The non-contact optical detection is morepreferable for detecting these waves induced in the eye tissues comparedto detection by ultrasound transducers because it minimizes discomfortfor the patient.

Example 7

A time-resolved optical system (FIG. 9) can be used for glucosemonitoring in the tissues, preferably the tissues of the eye. The systemgenerates ultrashort (typically femtosecond) optical pulses, directs thepulses to the tissues, and detects the pulses reflected from tissuelayers. The system measures the time of flight of the optical pulses andconverts them into blood glucose concentration.

Example 8

An optical system for generating short, broad-band ultrasound pulses inan optically absorbing medium (FIG. 11) can be used for glucosemonitoring. The medium is attached to the skin surface. The opticalsystem produces at least one short (typically nanosecond or picosecond)optical pulse and directs it on the absorbing medium. The energy of theoptical pulse is absorbed by the medium that results in generation of ashort ultrasound (acoustic) pulse. The ultrasound pulse then propagatesin the tissue and is reflected from tissue layers. An ultrasoundtransducer detects the reflected ultrasound pulses and a processoranalyzes the signal from the transducer and calculates the time offlight of the ultrasound pulses and glucose concentration.

A short (typically nanosecond) radiofrequency electromagnetic pulse canbe used instead of the short optical pulse to generate a short,broad-band ultrasound pulse in a radiofrequency absorbing medium.

An optical detection of the reflected ultrasound pulses can be used.

The existing techniques for glucose monitoring are invasive. For last 20years many noninvasive glucose monitoring techniques have been proposed,however they suffer from insufficient accuracy, sensitivity, andspecificity. At present, there is no noninvasive glucose monitor on themarket.

The methods of the present invention can be practiced so that themeasurements include attenuation, phase, and frequency of the reflectedand incident beams or beam pulses.

REFERENCES CITED IN THE INVENTION

-   Ziebarth N., Manns F., Parel J.-M. Fibre-optic focus detection    system for non-contact, high resolution thickness measurement of    transparent tissues. Journal of Physics D: Applied Physics, 2005, v.    38, pp 2708-2715.-   Furushuma M., Imazumi M., Nakatsuka K. Changes in Refraction Caused    by Induction of Acute Hyperglycemia in Healthy Volunteers. Japanese    Journal of Opthalmology, 1999, v 43, pp 398-403.-   Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters P J.    Insulin therapy protects the central and peripheral nervous system    of intensive care patients. Neurology. 2005 Apr. 26; 64(8): 1348-53.-   Vanhorebeek I, Langouche L, Van den Berghe G. Glycemic, and    nonglycemic effects of insulin: how do they contribute to a better    outcome of critical illness? Curr Opin Crit Care. 2005 August;    11(4):304-11.-   van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,    Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R.    Intensive insulin therapy in the critically ill patients. N Engl J    Med. 2001 Nov. 8; 345(19):1359-67.

All references cited herein are incorporated by reference. Although theinvention has been disclosed with reference to its preferredembodiments, from reading this description those of skill in the art mayappreciate changes and modification that may be made which do not departfrom the scope and spirit of the invention as described above andclaimed hereafter.

1. A method for noninvasive glucose sensing including the steps of:measuring a thickness of a target tissue and determining a glucose valuefrom the thickness of the target tissue in accordance with a targettissue thickness calibration curve.
 2. A method for noninvasive glucosesensing including the steps of: measuring a time of flight of ultrasoundor optical pulses in a target tissue and determining a glucose valuefrom the time of flight in the target tissue in accordance with a timeof flight versus glucose calibration curve.